Spray drying is widely used in pharmaceutical manufacturing to produce microspheres from solutions or suspensions. The mechanical properties of the microspheres are reflected by the morphology formed in the drying process. In suspension drying, solids dissolved in the carrier liquid may form bridges between the suspended primary particles, producing a microsphere structure which is resistant against mechanical loads. Experiments with individual, acoustically levitated droplets were performed to simulate the drying of suspension droplets in a spray drying process.

Introduction

Single droplet drying and particle formation during spray drying are difficult to investigate, because of the complex two-phase flow in spray dryers and other difficulties [1]. A technique to investigate single droplet drying is acoustic levitation, where single droplets can be placed close to the pressure nodes of a standing acoustic wave. The first drying stage is known as the constant-rate period, since the surface of the droplet decreases at a constant rate due to evaporation of the liquid from the surface. This drying stage therefore follows the so-called d2 law [2]. Suspension droplets exhibit this behavior as long as the surface is wetted [3]. At high ratios of droplet-shrinkage-rate-to-diffusivity in the liquid phase, a non-uniform radial distribution of the solid may arise, leading to crust formation [4]. The local porosity of the solid, surface roughness and solids distribution inside the microsphere may result in a highly complex evolution of the second drying stage [4].

In the present work we studied the evaporation kinetics of suspension droplets, with solids dissolved in various carrier liquids, and the resulting microsphere morphology of pharmaceutical excipients. Furthermore, the mechanical properties of individual microspheres were evaluated by hardness measurements and related to the solid’s solubility in the liquid. Knowing the influencing factors during spray drying of suspensions will make it possible to choose process parameters during drying which avoid change of particle properties.

Materials and methods

Lactose GranuLac® 230 (Molkerei Meggle, Wasserburg, Germany) was used as solid substance, and water of analytical grade (Ultrapure water system TKA, Niederelbert, Germany) and isopropanol in high purity ≥ 99.8 % (Carl Roth, Karlsruhe, Germany) as liquid mixture to form the suspension. The ratio of water-isopropanol was varied according to the solubility curve in Figure 1, resulting in different amounts of dissolved lactose. Lactose exhibits a high solubility in water and a low solubility in isopropanol. The following definitions were chosen, i.e., the mass of the liquid mixture mliq consisting of H2O and solvent I (isopropanol) in Eq. 1, the water mass fractionwH2O in Eq. 2 and the solubility of lactose XL in Eq. 3 with md as the mass of the dissolved excipient (alpha-lactose monohydrate).

An acoustic levitator was used to assess the drying kinetics of lactose suspensions with different lactose mass fractions and solvent compositions. This technique enables drying without contact between the levitated object and a solid body, and therefore heat and mass transfer are influenced only from the acoustic streaming which can be controlled by additional air streams around the object. The levitation setup used can be seen in Figure 2, consisting of a transducer and reflector to generate the acoustic sound wave for droplet positioning, and a macro lens with a light source to record the drying progression.

The composition of a droplet with the mass m consists of the dissolved mass md and the suspended mass ms of the solid material in a mixture of the liquid masses mH2O and mI of water and isopropanol. Depending on the water mass fraction wH2O (Eq. 2), different mass of solids msolid (Eq. 4) were present in one suspension droplet. The solids mass msolid consists of dissolved md and suspended solids ms.

In terms of definition, the mass m was used as reference to define the dissolved solid mass fraction wd (Eq. 5), the suspended solid mass fraction ws (Eq. 6) and the total solid mass fraction wsolid (Eq. 7).

Table 1 shows the investigated suspension compositions with variations in the suspended lactose mass fraction ws from 10 % to 50 %. Afterwards, the measurement series was continued with the same suspended lactose mass fraction ws of 10 % and varying dissolved lactose mass fractions wd , ranging from 0.0072 % to 17 %. These variations are due to different water mass fractions wH2O, ranging from 0 % to 100%.

Table 1. Compositions of suspensions for drying experiments.

The hardness of individual microspheres was measured with the side-crushing-strength (SCS) test in a slightly modified version. The procedure for this test method is described in ASTM Standard D4179-01 for crushing of single catalyst pellets [5]. The agglomeration strength of individual dried microspheres was measured using a rheometer MCR 300 from Anton Paar (Graz, Austria) in the plate-plate configuration. For this measurement, individual microspheres dried in the acoustic levitator were placed in the center of the bottom plate, and the upper plate was moved downward at the constant velocity of 5 x 10‑6 ms-1 (see Figure 3). The normal forces were recorded while the upper plate was moving.

Figure 3. Microsphere on the rheometer plate (a) before and (b) after hardness test.

Results and discussion

Individual droplet drying experiments were performed for the fixed suspended lactose mass fraction ws of 10 % and different compositions of the carrier liquid of the suspension. The varying liquid compositions (water mass fractions wH2O from 0 % to 70 %) exhibit different solubility of lactose, and therefore, resulted in different dissolved lactose mass loadings Xd from 0.072 % to 34.4 %. Figure 4 depicts the drying of individual droplets with the same suspended lactose mass fraction ws of 10 % and different compositions of the carrier liquid. The drying air flow with 0.66 m/s (Re = 170) was applied to control the vapor content of the acoustic streaming vortices. The drying of an individual droplet consisting of lactose and isopropanol without water revealed the fastest evaporation rate in the first drying stage. Adding water to the droplet liquid reduced the evaporation rate, resulting in a longer first drying stage. These drying kinetics of binary liquid mixtures are due to the different activities of the two liquid components, which furthermore depend on the composition of the liquid phase.

Another effect that reduces the drying rate at higher amounts of dissolved solid is the formation of bridges and shells. The amount of dissolved solids increased with the water content of the liquid, resulting in a higher total solid loading in the droplet. The dissolved solids precipitated during the drying process and formed bridges between primary particles or a skin on the surface, which reduced the rate of evaporation of the volatile components [6]. At low concentration, the dissolved solids formed a porous structure allowing for fast solvent evaporation. In contrast to this, high amounts of dissolved solids precipitated at the surface and sealed the pores, hindering the evaporation of the liquids.

The electron micrographs in Figure 5 depict the surface and bulk morphologies of microspheres dried in the levitator with the constant suspended lactose mass fractionws of 10 % and different dissolved lactose mass loadings Xd between 5.3 % and 34.4 %. For low levels of Xd no significant effects of the dissolved solid could be observed, and primary particles had no visible connections by precipitated material. Raising the water mass fraction wH2O to 30 % and, therefore, the dissolved lactose mass loading Xd to 6.1 %, resulted in visible connections of the primary particles with precipitated solids on the surface (Figure 5b(i)). The precipitated mass acts as a binder and “glues” the primary particles together, resulting in a more densely packed network structure. The particle packing at the droplet surface becomes more intense as the dissolved lactose mass loading Xd increases to 14.4 % (Figure 5c(i)). An additional increase of Xd can even lead to full covering of the microsphere surface with precipitated solids (Figure 5d(i)). At the dissolved lactose mass loading Xd of 34.4 %, no primary particles were visible any more.

The mechanical strength of microspheres produced by acoustic levitation was measured with the SCS test in a slightly modified version. Figure 6 depicts characteristic profiles of the normal force on individual particles, produced and measured by the rheometric device. The first change in the normal force is observed as the upper plate takes up contact with the microsphere. This contact point indicates a typical dimension of the microsphere of 685 µm. Thereafter, the normal force increases rapidly until a maximum force is reached, which indicates the force needed for breaking the microsphere and, therefore, the mechanical strength of the object against normal stress. As the microsphere breaks, the recorded force decreases immediately. Further linear motion of the upper plate leads to normal forces due to the compression of the fragmented microsphere.

Figure 6. Normal force on individual microspheres dried in the acoustic levitator as a function of plate distance. The normal force is applied and recorded by a rheometer. The suspended lactose mass fraction ws was 10 %. The dissolved lactose mass loading Xd varied between 5.5 % and 8.7 %.

The first measurable breaking force was obtained for the dissolved lactose mass loading Xd of 5.3 %, as depicted in Figure 7a. Small changes in the dissolved lactose mass loadings Xd from 5.5 % to 6.1 % resulted in an increase of the breaking force. More dissolved solids connected the primary particles, resulting in stronger bonds and a significant increase of the breaking force within this transition zone. Increasing dissolved lactose mass loading Xd up to 6.1 % resulted in the formation of stronger agglomerates between primary particles, revealing a stronger increase of the breaking force. The same relation is observed by depicting the breaking force as a function of the water mass fraction wH2O in the suspension, as in Figure 7b.

Based on these data, by extrapolation the point was calculated where no force is needed to break the microsphere. This point reflects a suspension composition with a dissolved lactose mass loading Xd of 5.2 % or, equivalently, a water mass fraction wH2O of 19 %. This corresponds to our observation that quite loose microspheres are formed below these values. These results demonstrate the strong influence of the suspension composition on the mechanical strength of spray-dried particles. There exists a threshold value of the dissolved lactose loading Xd below which loose microspheres are formed. Primary particles are then loosely bonded by precipitated solids, so that the microspheres easily break up, even by weak forces.

Figure 7. The breaking force as a function of (a) the dissolved lactose mass loading Xd and (b) the water mass fraction wH2O.

Conclusions and Outlook

The present work investigates the influence of initial suspension droplet composition on the drying kinetics via acoustic levitation and the resulting microsphere properties in relation to spray drying. It is found that the dissolved lactose mass loading Xd determines the drying kinetics and has a strong influence on the dried microsphere morphology and mechanical strength. The individual microsphere structure changes from loosely packed primary particles with isopropanol as the solvent to denser packing with increasing water mass fractionwH2O. The dissolved solids precipitate during drying and bond the primary particles. The hardness of individual microspheres was measured by a compression strength test. Loosely agglomerated microspheres were formed below the threshold Xd = 5.2 % for the investigated model substance. Based on these findings, drying should be carried out below this threshold to enable drying either of primary particles (i.e. tailored particle properties after crystallization remain unaltered during drying), or above this threshold to produce larger, agglomerated particles (i.e. improved powder flowability as favored in direct compression).

Since this study was focused on only one suspension composition with an excipient as model substance, further research will be conducted with various APIs and solvent combinations. In the end, the sum of experimental data could be used to predict the microsphere strength based on the suspension composition.

One of the biggest problems in the manufacturing of high-quality low-dose inhalation products, is dose uniformity of filled capsules [1]. Our approach towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling comprises a decoupling of the filling process in dynamic and static mode tests, whereas the latter was carried out using a novel filling system, i.e. stand-alone static test tool, developed by us.

Introduction

Precise dose filling in the lower mg-range, which is required for inhalation therapies [2], is essential for the successful manufacturing of high-quality products. Filling inhalation powders into capsules often requires specialized equipment that can handle the very low fill weight [3] in the range of a few tens of milligrams. For the currently available low-dose capsule filling systems, the dosator method is often used [4]. To date, although there is a considerable body of literature on identifying and assessing critical material and process parameters that affect the product quality for standard doses, little attention has been paid to low-dose dosator capsule filling processes. Recent studies of our working group [4, 5] demonstrated that the low-dose filling of very fine carriers with a dosator system is challenging, and further investigations are needed in order to achieve the required product specification compliance. Therefore, we developed a stand-alone static test tool with two primary aims:

to investigate the effect of gaps between the dosator tip at the end of the stroke and the bottom of the powder container box (Figure 1) with different carrier materials. Although this process parameter is expected to affect the fill weight and weight variability, it has received too little attention to date.

to take a closer look at the filling behavior of challenging fine carrier materials. It was assumed that the mechanical vibration of the powder drum induces particle movement/rearrangement in the drum and, possibly, segregation. To that end, the vibration present in the drum was measured to assess its intensity (specifically acceleration and frequency). Subsequently, the vibration was recreated in a laboratory setup to isolate the effect of vibrations, separating it from the dosing process and drum rotation.

Methods

Three grades of lactose excipients (Lactohale 100, Lactohale 200, Lactohale 220) that are commonly applied as carriers in inhalation therapies [2] were used as received from the supplier (DFE pharma, Goch, Germany). The various process steps of the capsule filling process were investigated by dynamic and static mode tests. Dynamic tests refer to filling of capsules in a regular lab-scale, low-dose dosator capsule filling machine (Labby, MG2, Bologna) with special low-dose equipment adaptions (i.e., smaller nozzles, a cleaning unit for the removal of excess powder from the dosator and special blades to create the powder layer). Static tests were conducted using a novel filling system developed by us. In both cases powders were filled into size 3 transparent hard gelatin capsules supplied by Capsugel with different dosing chamber lengths (2.5, 5 mm), dosator (nozzle) diameters (1.9, 3.4 mm) and powder bed heights (5, 10 mm), and, in the dynamic mode, with two filling speeds (500, 3000 capsules/h). The influence of the gap at the bottom of the powder container (Figure 1) on the fill weight and weight variability was assessed. Moreover, using an advanced experimental setup the effect of vibration on the filling performance of the highly cohesive Lactohale 220 was evaluated.

Figure 1: Sketch of the static test tool. The gap between the dosator tip and the bottom of the container are shown.

Results and Discussion

Results of different gaps indicated that, generally, the fill weight of all three powders in question was affected by varying the gaps, but in different ways. The most significant changes in the fill weight were observed for the highly cohesive powder, with a distinct correlation between the gaps and the fill weight: the smaller the gap, the higher the fill weight (Figure 3). Another significant finding of the static mode test was that with a low gap it was possible to fill the highly cohesive powder within a wide range, from 6 mg to 20 mg, with RSDs below 10% without any pre-compression. This is important with regard to filling capsules with very fine powders since compressing the powder into the dosator may lead to jamming the piston, blocking the dosator and terminating the process.

Interestingly, in terms of vibration no change in the fill weight of the highly cohesive powder over time, as previously reported Stranzinger et al. [5], was observed in the static mode dosator dipping tests. This may be explained by the different modes of applied vibration (i.e., horizontal and vertical vibration), different sampling conditions and different powder layer re-conditioning strategies. One of the most striking observations to emerge from our study is that the sampling method, i.e., sampling with or without vibration, plays a key role in terms of weight variability. When using our new approach “dosing under vibration” a significant reduction of weight variability can be achieved. More precisely, for the highly cohesive powder the weight variability was reduced from 14.0% RSD to 4.5% RSD for adjusted vibration (i.e. vibration present at a capsule filling speed of 3000 capsules/h in dynamic mode) and from 18.8% RSD to 6.5% RSD under more intense vibration.

Overall, our results indicate that by fine-tuning instrumental settings even very challenging powders can be filled with a low-dose dosator capsule filling machine. This study is a further step towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling.

Conclusion and Outlook

The findings suggest that for low-dose dosator capsule filling it is strongly recommended to continuously control instrumental settings, i.e., gaps between the lowest point of the dosator and the bottom of the box, as well as vibration that clearly affects the fill weight and weight variability. Researching the effect of certain process parameters of various powder materials on the filling performance provides valuable insights into a dosator nozzle filling process, step by step. Our results could help machine manufacturers to achieve product-specification compliance by fine-tuning the process parameters depending on the powders used.

Since this study was focused on the filling performance of pure carrier material, further research should be conducted to investigate the filling behaviour of powder mixtures (e.g., a powder with an API). In the end, a stepwise mechanistic process understanding could be developed, with the ultimate goal of creating a platform indicating the required instrumental settings for a range of various materials.

1. Introduction

Cold compaction of powder is important for many industrial processes, e.g., for the production of green bodies before sintering of metallic or ceramic parts in mechanical engineering, pellets for mineral or animal food industry or the production of tablets in the pharmaceutical industry. The final powder compact requires a minimum strength as otherwise it would disintegrate during processing, transportation or storage. Experiments can be used to adjust the process to get the desired compact strength. This is time-consuming, as process parameters change often, e.g., the geometry of the machine tools or the powder properties. Hence, reliable numerical models to predict the properties of compacts with simulations are crucial.

2. Method

The multi-particle finite element method (MPFEM) is used to model the yield strength of compacted powder. This approach considers discrete particles by treating each single particle with FEM. The meshed particles may deform according to some elasto-plastic material law and interact with each other via contact mechanics [1–3]. The disadvantage of this method are the very high computational costs, and therefore in this work only a small representative volume element RVE with a certain number of particles is considered (see Figure 1 left). Periodic boundary conditions are used to avoid boundary effects. This “micromechanical” model is used to determine yield surfaces of the powder, which are comparable to well-known Drucker-Prager/Cap model (see Figure 1 right). During the parameter study the relative density of the powder after compaction and the cohesion strength of the particle contacts is varied. The details of the model can be found in [4].

Figure 1: The RVE of deformable particles (left) is used to determine yield surfaces similar to the Drucker-Prager/Cap model (right)

3. Results

Figure 2 presents the numerically obtained yield surfaces for different relative densities with a constant cohesion strength (filled points). As expected, the size of the yield surfaces increases with increasing relative density, while the shape remains approximately constant. The solid lines are least-square error fits of Eq. 1 to the discrete data points. The equation uses five fitting constants (a, pm, r, j, t, k) to describe different sizes and shapes of the yield surface. As can be seen in the figure, a very good fit is achieved.

Figure 2: Yield surfaces of compacted powder for different relative density after compaction and a constant contact cohesion strength of 100 MPa

Figure 3 depicts the numerically modeled yield surfaces as a function of the cohesion strength with a constant relative density of 0.85. An interesting behavior can be observed here: Low cohesion strengths cause yield surfaces that match the shape of the Drucker-Prager/Cap model. In contrast, high cohesion strengths result in an elliptical shape. The ellipse is remarkably similar to the isotropic constitutive model for the plastic behavior of metallic foams developed by [5]. The center of the ellipse is close to a pressure of zero, which requires the isostatic compressive strength to be equal to the isostatic tensile strength. Such a behavior can be explained by practically bonded particles. The high contact cohesion inhibits contact sliding and particle rearrangement and therfore the plastic yielding of the particles is mainly responsible for the deformation of the powder, which renders the powder’s behavior similar to a foam or porous material. The solid lines are again least-square error fits of Eq. 1 to the discrete data points.

Figure 3: Yield surfaces of compacted powder for different contact cohesion strength cmax and a constant relative density of 0.85.

4. Conclusion and Outlook

This work introduces an efficient RVE for the compaction simulation of a monodisperse powder with the MPFEM. In contrast to earlier studies cohesion is considered in the particles’ contact, which allows to describe tensile strength after compaction. The present work shows the influence of different cohesion strengths on the yield surface of compacted powder. The model allows to run multiple parameter studies. Hence it is possible to determine yield surfaces as a function of the compact density and the cohesion strength.

Although the existing work demonstrates the possibilities of MPFEM for compaction simulations there are further steps necessary to fully exploit the possibilities of this method in the future. Non-ideal conditions of real particles (non-spherical and polydisperse particles, etc.) have to be taken into account to describe real powders. The deformation behavior of the particle material (elastic, plastic and fracture) as well as the real contact interactions between particles have to be modelled sufficiently to obtain numerical results which can be compared to real experiments. Next, different compaction modes could be considered in future work since only isostatic compaction was considered in this work. Especially closed-die compaction should be considered, since it is representative for many industrial compaction processes as for example tableting.

Particle production based on supercritical carbon dioxide (scCO2) is efficient, inexpensive, and ecological [1]. These kinds of bottom-up technologies form particles by re-crystallization. CO2 is the most common solvent in supercritical processes, since its critical temperature and pressure are relatively low, 74 bar and 31°C [2]. Furthermore, CO2 is ‘Generally Recognized As Safe’ (GRAS) by FDA; it is neither flammable nor toxic.

Particle production techniques employing scCO2 use scCO2 as solvent, as solute or as anti-solvent [3]. Rapid Expansion of Supercritical Solutions (RESS) is a solvent- and excipient-free production method [4]. It has been mainly used to produce micron and submicron particles in pharmaceutics.

The processes using scCO2 as a solvent have been modified by changing process parameters. However, since invented, particle production using scCO2 as solvent is based on rapidly decreasing the pressure [5]. The rapid decrease of pressure has been considered essential for formation of small particles.

Method

Our experiments indicate that nanoscale particles can be produced in opposite conditions to the existing RESS technique: slow depressurization and with low degree of supersaturation, using a method called Controlled Expansion of Supercritical Solution (CESS). Experimental apparatus was built for CESS experiments (Figure 1). CESS differs from RESS in many respects and employs controlled mass transfer, controlled flow, controlled pressure reduction, and finally particle collection in dry ice (Table 1). The core of the technology is to allow larger initial nuclei size and particle growth by condensation. This avoids the variation in temperature, pressure, and density, as well as the particle growth by coagulation.

Figure 1. Experimental apparatus used to produce nanoparticles.

Table 1. Essential differences between RESS and CESS techniques.

RESS

CESS

Pressure drop

rapid

controlled

Ratio of pressure drop

>10

<10

Flow velocities

supersonic

subsonic

Degree of supersaturation

high

low

Formation of Mach disk

yes

no

Particle formation

mainly beyond exit nozzle

mainly prior to exit nozzle

Main mechanism for particle growth

coagulation

condensation

In RESS the supercritical solution is expanded through a nozzle and the subsequent rapid decrease in solvent density reduces the solvent power [4]. Particles are generated as solute precipitates and the particle formation, the creation of a single spherical particle of radius r, can be understood using the reduced Gibbs energy in a closed system (Equation 1) [6].

(1)

Here ΔG(kT)-1 is the reduced Gibbs energy, k Bolzmann’s constant, T temperature, σ the interfacial tension of the solute, v2,s the molecular volume of the solid phase, p2 the partial pressure of the solute, and S the supersaturation. The parameter to alter in the expansion of a supercritical process is the supersaturation (Equation 2) [7].

(2)

Here, y2,E(TE,pE) is the mole fraction of the solute at post-expansion temperature and pressure, y*2(T, p) is the equilibrium mole fraction of the solute at the extraction temperature and pressure, and Φ2 the solute fugacity coefficient relating the ideal gas pressure and the effective pressure of a real gas. The molar ratios determining the degree of supersaturation directly depend on the pre- and post-expansion pressure and temperature. A steep drop in pressure and temperature decreases the density and solvent power of CO2 significantly, resulting in a high degree of supersaturation. The higher the degree of supersaturation, the more numerous and smaller are the formed nuclei [8].

After nuclei formation, particles grow by two mechanisms: condensation where free molecules are deposited onto the nuclei surface, and coagulation where particles grow by colliding [9]. In RESS the time available for particle growth by condensation is limited to microseconds.

In RESS, the ratio of pre-expansion to post-expansion pressures exceeds 10, the ejection velocity is sonic at the nozzle, and later supersonic [10]. The supersonic free jet ends with a Mach disk beyond which the velocities again are subsonic. Particle precipitation in the RESS process mainly takes place after the nozzle exit and in the shear layer of the jet [11]. The particle concentration is highest at the Mach disk and the main mechanism for particle growth is coagulation in the subsonic free jet. The flow in the collection chamber of a RESS system is often rather chaotic.

In CESS the focus is on achieving lower degrees of supersaturation, slow velocity and limited mass transfer. The ratio of pressure before and after each pressure drop is kept below ten. This prevents the flow speed beyond the nozzle from reaching sonic velocity, and thus there is neither a Mach disk nor density differences in the collection chamber as in the RESS process. Consequently, particle growth by coagulation is reduced. Particles form under mild conditions prior to the exit nozzle and grow mainly by condensation. Particle formation and growth is thus much slower than in RESS and the particles form in a controlled environment.

The CESS process itself is more robust, stable, and reproducible, than the RESS process; the pressure and flow as well as the production rate are constant and the environment for particle formation between processes is identical. In contrast to RESS, small changes in the initial pressure and temperature do not affect the end-product. The CESS process produces small particles successfully without use of co-solvents, excipients, or collection into aqueous media.

Results

The pressure, flow, and the rate of solid dispersion formation within the collection chamber are constant. Hence the collection and particle production processes are stable. The robustness, stability, and reproducibility of the process were proven by preparing 3 batches of the same product. The SEM images obtained from different parts of each sample indicate that the nanoparticles prepared from piroxicam were monodisperse in size and shape. The average nanoparticle diameter was 176 nm ± 53 nm, the batches 169 ± 48 nm (n=300), 179 nm ± 54 nm (n=300), and 179 nm ± 67 nm (n=300) (Figure 2). The particle size of the bulk was 7106 ± 5639 nm (n=300).

The article is based on the publication “Controlled Expansion of Supercritical Solution (CESS): a robust method to produce pure drug nanoparticles with narrow size-distribution” (J Pharm Sci 2016; 105(8); 2293-2297) by Jenni Pessi, Ilkka Lassila, Antti Meriläinen, Heikki Räikkönen, Edward Hæggström and JoukoYliruusi. Jenni Pessi, Heikki Räikkönen and JoukoYliruusi are from the Formulation and Industrial Pharmacy Unit of Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki. Ilkka Lassila, Antti Meriläinen and Edward Hæggström are from the Division of Material Physics, Department of Physics, University of Helsinki.

Formulation and Industrial Pharmacy (FIP)

The FIP research unit focuses on the translation of a drug molecule into a medicine. The aim is to maximise the quality and feasibility of the medicine by understanding all the factors that affect product development, including pharmaceutical material properties, processing, stability, and end user needs. Research focuses of FIP are solid state engineering, molecular based formulation science, processing technology, and industrial pharmacy research.

Written by Kitti Csordas, early stage researcher in the IPROCOM project

Introduction

Heat or moisture sensitive active pharmaceutical ingredients requires a processing chain, which does not require water or organic solvents. Roll compaction/dry granulation is a suitable process for this purpose that provides additional advantages, e.g. increase of bulk density, improvement of flowability and reduction of manufacturing cost [1]. Due to the growing interest of the understanding of this granulation process, the IPROCOM project ‘The development of in silico process models for roll compaction’ brought together several research groups, e.g. Heinrich Heine University, Duesseldorf and Research Center of Pharmaceutical Engineering, Graz that are also members of PSSRC. The purpose of the project is the deeper understanding of fundamental mechanisms of particulate manufacturing processes involving roll compaction. In this work introduced below, results are exhibited obtained in one of the 15 main topics in the IPROCOM project [2].

In the framework of IPROCOM, different types of roll compactors were used in order to compare their control performance. Mannitol ribbons were produced using an AlexanderWerk BT120, an L.B. Bohle BRC 25 and a Gerteis Mini-Pactor roll compactor. The accuracy and precision of the specific compaction force or hydraulic pressure and gap width were examined. The best results for accuracy, precision and adaptation time of the process data was found in case of the tested Mini-Pactor, while the investigated BRC 25 roll compactor provided slightly less accurate and precise control in the actual test setting. In case of both roll compactors the gap width was controlled by a PI-control loop. Due to the lack of any gap control system, the least accurate process data were obtained compacting with the tested AlexanderWerk BT120.

Materials and methods

Spray-dried mannitol (Pearlitol 200 SD, Roquette, France) as brittle model substance was roll compacted. The bulk powder was compacted by different types of roll compactors without using any type of lubricant in order to avoid its effect on the roll compaction process. An AlexanderWerk BT120 (AlexanderWerk, Germany, year 2008), a L.B. Bohle BRC 25 (L.B. Bohle, Germany, year 2015) and a Gerteis Mini-Pactor (Gerteis Maschinen+Prozessengineering, Switzerland, year 1999) were used to investigate the process control performance thereof. Knurled roll surface was used during all roll compaction runs. The roll compactor configurations are presented in Figure 1.

The AlexanderWerk roll compactor does not have any control system, thus the gap width was dependent on the screw speed and roll speed. The hydraulic pressure was adjusted by the hydraulic system. The BRC 25 set the specific compaction force through a spindle motor [6], while the gap size was controlled by a PI control system. The PI parameters of the gap width control loop were set at P: 10 and I: 20 s. In case of Mini-Pactor, the specific compaction force was adjusted by the hydraulic system and the gap width was controlled by a PI control loop (automatic mode) that was set at P: 12 s and at I: 15. The mean and the standard deviation of the process parameters were calculated, when the process parameters achieved the specifications described below, thus steady-state process condition was realized. The effect of specific compaction force and hydraulic pressure were tested at five settings, while the gap size was adjusted to 1.5 mm or 3.0 mm. The feeding screw speed was changed between 10 – 70 rpm, thus the tamping screw speed was set between 20-140 rpm. The experiments were conducted according to the principles of design of experiment following multilevel full factorial experimental plan in case of each roll compactor. The data recording frequency was set at 0.1 Hz, when AlexanderWerk BT120 was used, while in case of BRC 25 a frequency of 7-9 Hz was adjusted. The data obtained using Mini-Pactor showed a recording frequency of 1 Hz.

Results and discussion

The defined specification of the hydraulic pressure is set at the setpoint HP ± 2 bar and at the setpoint GW ± 0.1 mm, when AlexanderWerk BT120 is used. According to these terms, the accuracy and precision of the hydraulic pressure and gap width adjustment are inappropriate to produce ribbons with proper quality, presented in Table 1. In case of 18 bar and 60 bar hydraulic pressure setting 3.0 mm gap width, the actual values (20.43 ± 0.50 bar and 58.07 ± 0.33 bar) of the hydraulic pressure are out of specification. The gap width is least accurate and precise, when 18 bar hydraulic pressure and 1.5 mm gap width are set, as exhibited in Figure 2. 0 s settling times regarding 18 bar hydraulic pressure are obtained, while 10 s is needed to increase the hydraulic pressure from 36 bar to 60 bar independently of the set gap width. 0.1 Hz data recording frequency does not allow to have more detailed information about the settling time. Immediately, after setting 18 bar hydraulic pressure, 18 bar as actual value is observed, when 1.5 mm gap is set. Since the previous set hydraulic pressure is 18 bar, 0 s adaptation time of the hydraulic pressure is determined, when 3.0 mm gap width is set. The settling time of the gap width is observed between 30-70 s.

Figure 2. Change of the hydraulic pressure from 24 bar to 18 bar and gap width from 3.0 mm to 1.5 mm for AlexanderWerk BT 120.

Compacting with BRC 25, the adjustment of the specific compaction force has priority to the gap width control. Thus, the obtained periods of time needed to change the gap width are longer compared to the time required to set the specific compaction force. The specification of the specific compaction force is the set value SCF ± 0.1 kN/cm and for the gap width set value ± 0.1 mm. The specific compaction force is adjusted precise but not perfectly accurate, presented in Table 2. The specific compaction force is found to be within the specification, when 2 kN/cm specific compaction force and 3.0 mm gap width are set. The gap width adjustment is observed accurate and precise, except setting 3.0 mm gap width and 10 kN/cm specific compaction force. The mean of the gap size is calculated to be 3.05 ± 0.11 mm, which is above the defined threshold. The smaller the difference between the previous and the new gap width, the less adaptation time is necessary to achieve steady-state process conditions. Increasing the gap width from 2.3 mm to 3.0 mm takes 24 s, while the increase or decrease of gap width with 1.5 mm requires 42-48 s. The settling time of the specific compaction force is obtained between 15-38 s. In Figure 3, the increase of the hydraulic pressure from 6 kN/cm to 10 kN/cm and the decrease of the gap width from 3.0 mm to 1.5 mm is plotted. To decrease the gap width, first the speed of the feeding and tamping augers are decreased and then increased by the PI control loop till the set gap width is achieved as actual value. The specific compaction force shows an increasing-decreasing trend, before the constant value is achieved.

For the Gerteis Mini-Pactor the specification of the specific compaction force is the set value SCF ± 0.1 kN/cm and for the gap width set value ± 0.1 mm. The obtained gap widths and the time required to achieve the steady-state processing condition are listed in Table 3. The actual values of specific compaction force and gap width are found to be the most precise and accurate. The adaptation times are obtained under 16 s regarding specific compaction force, while the longest settling time of gap width is 8 s. In Figure 4 the roll compaction process in automatic mode is introduced showing smooth specific compaction force and gap width trends.

Conclusion

It is difficult to obtain a desired gap width without a gap control during roll compaction. Thus, the process has poor accuracy and precision, when AlexanderWerk BT120 roll compactor is used. When the process is tested using BRC 25, it is not always possible to obtain the desired specific compaction force, however appropriate precision of the specific compaction force is achieved due to the spindle motor configuration. The observed deviation of the specific compaction force is marginal compared to the determined deviations of hydraulic pressure provided by AlexanderWerk BT120. The most accurate and precise process is determined, when Mini-Pactor is used in automatic mode. The settling time of the gap width is found to be shorter compared to the BRC 25 roll compactor, which is explained through the PI control loop adjustments of the Mini-Pactor. Compared to BRC 25, the Mini-Pactor reacts stronger to gap width changes due to the higher P-portion and the more frequent control steps and distinctive response of the gap width values due to the lower I-portion, a more consistent process and faster process adaptation are obtained in case of Mini-Pactor operating in automatic mode.

PSSRC Facilities

Beside extrusion and coating processes, the working group of Professor Peter Kleinebudde does research on roll compaction/dry granulation. The understanding of the roll compaction process is of main interest, considering the effect of material properties, process parameters, control systems and scale on roll compaction. A further aim of research is the development of PAT tools measuring the ribbon relative density and granule size distribution as critical quality attributes of roll compaction.

Acknowledgements

This work was supported by the IPROCOM Marie Curie initial training network (www.iprocom.org), funded through the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/ under REA grant agreement No. 316555.

Poly(lactic-co-glycolic acid) (PLGA)-based microparticles offer a great potential as parenteral controlled drug delivery systems [1]. Different types of drug release patterns can be obtained from PLGA microparticles, in particular mono-, bi-, or tri-phasic drug release kinetics. Interestingly, yet the underlying mass transport mechanisms in PLGA microparticles are not fully understood, despite their great practical importance. This can be attributed to the complexity of the involved mass transport mechanisms. The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. Importantly, new insight was gained based on the experimental monitoring of the swelling kinetics of single microparticles.

Initially, PLGA microparticles loaded with ketoprofen were prepared using O/W emulsion extraction / evaporation solvent method while keeping the other parameters constant for different formulations. The only parameter which was varied is the viscosity of the organic phase. The aim is to get a range of microparticles having the same size. The obtained microparticles were thoroughly characterized using several techniques such as GPC, DSC and X-ray powder diffraction. The in vitro drug release studies were performed in phosphate buffer pH 7.4 (containing 0.02 % Tween 80) at 37 ° C with horizontal shaking. At predetermined time intervals, samples were withdrawn, replaced with fresh medium and analyzed by appropriate method. Swelling studies were monitored in 96-well standard microplates in the same conditions as the release studies.

Key properties of microparticles

The obtained results showed that the encapsulation efficiency of the investigated ketoprofen-loaded microparticles substantially increased (from 50 to 90%) when increasing the theoretical drug content from 1 to 50 %. The release studies showed two types of release profiles as it can be seen in Figure 1.

(reprinted with permission from [4])

At low drug loadings, tri-phasic drug release patterns were observed: After an initial rapid release phase (“burst release”), a release period with a more or less constant drug release rate was observed, followed by a third (and again rapid) drug release phase. With increasing drug loadings the onset of this third release phase was shifted to earlier time points. At high drug loadings, it was difficult to clearly distinguish different drug release phases; the profiles were more or less bi- or mono-phasic. To better understand why these pronounced differences in the drug release patterns were observed and in order to elucidate the underlying mass transport mechanisms controlling ketoprofen release from these PLGA microparticles, the latter were thoroughly characterized before and after exposure to the release medium. The X-ray powder diffraction patterns of the PLGA, ketoprofen and the different types of drug loaded PLGA microparticles were performed before exposure to the release medium. Clearly, the ketoprofen powder as received was highly crystalline, whereas neither the PLGA powder (as received), nor any of the ketoprofen-loaded PLGA microparticles showed X-ray diffraction peaks indicating crystallinity. This means that the ketoprofen, which was dissolved in the organic phase during microparticle preparation, did not re-crystallize upon solvent evaporation, but was probably molecularly dispersed in the PLGA matrix (dissolved) and optionally partially precipitated in an amorphous form within the system (depending on the practical drug loading). DSC measurements with dry, ketoprofen-loaded microparticles confirmed this hypothesis: The pure ketoprofen powder (as received) showed a sharp melting peak at about 95 °C, whereas none of the investigated ketoprofen-loaded PLGA microparticles showed any thermal event in this temperature range. This is also in good agreement with data reported by Ricci et al. [2]. Furthermore, the DSC studies revealed that ketoprofen is an efficient plasticizer for PLGA. Figure 2 shows how the glass transition temperature (Tg) of the polymer significantly decreased upon addition of up to around 25% ketoprofen. Blasi et al. attributed these plasticizing effects to hydrogen bonding [3].

(reprinted with permission from [4])

Figure 3 illustrates the impact of the initial practical ketoprofen loading on PLGA degradation in the investigated microparticles upon exposure to the release medium. As it can be seen, the polymer degradation rate substantially increased with increasing initial drug content. This can be attributed to the fact that ketoprofen is an acid and PLGA degradation is catalyzed by protons [4]. Importantly, the polymer molecular weight can be expected to be potentially decisive for key properties of the microparticles, such as their mechanical stability and swelling behavior.

(reprinted with permission from [4])

Swelling kinetics of individual microparticles and correlation with drug release

The microscopic pictures in Figure 4 show ensembles of microparticles, which were exposed to phosphate buffer pH 7.4 (containing 0.02% Tween 80) at 37 °C for 7, 10 and 14 d, respectively. Importantly, the spatial arrangements of the microparticles in the wells remained about constant, so that it was possible to follow the changes in the size of individual microparticles during the entire drug release period.

(reprinted with permission from [4])

The diagram in Figure 4 shows 3 examples: The swelling kinetics of a small microparticle (initially 55 μm in diameter), of a medium-sized microparticle (initially 83 μm in diameter) and of a large microparticle (initially 109 μmin diameter) are illustrated. Clearly, the microparticle size remained about constant during the first 7 d, and then substantially increased, irrespective of the microparticle size. This is likely attributable to the fact that after a certain lag-time, a critical PLGA molecular weight is reached, at which polymer swelling is less hindered. Initially, the degree of polymer chain entanglement is very high and effectively prevents substantial microparticle swelling. Upon contact with water, the polyester chains are more and more cleaved by hydrolysis and as soon as the degree of macromolecular entanglement becomes insufficient to prevent substantial particle swelling, the PLGA matrix can increase in volume. Also, the degradation products are creating a steadily increasing osmotic pressure within the system, attracting more and more water into the microparticles. Importantly, the observed dramatic changes in the microparticles' size result in tremendous changes in the systems' composition: the water content of the polymeric particles fundamentally increases. This can be expected to have major impact on the conditions for drug transport in the systems: The mobility of dissolved ketoprofen molecules is likely to substantially increase with the onset of significant microparticle swelling.

The same phenomenen was observed with microparticles loaded with 1.9 to 8.3 % of ketopofen. The lag-time was about 6 to 2 days, respectively and then the diameter of microparticles increased which coincide with the onset of the third drug release phase and the morphological changes are visible during this time period. In the case of microparticles loaded with 11.7 % to 35.0 % of ketoprofen (Figure 5), the onset of the third drug release phase was shifted to earlier time points when the drug loading increased and this can be probably due to the accelerates PLGA degradation in presence of hight amount of acidic drug.

(reprinted with permission from [4])

Conclusion

The presented results suggest that the swelling kinetics of PLGA microparticles can play a decisive role in the control of drug release: The onset of the often observed third (and again rapid) drug release phase form these systems might be a consequence of the penetration of substantial amounts of water into the particles, leading to a fundamental increase in drug mobility. During the second drug release phase, the polymer chain entanglement is too high to allow for significant particle swelling and, thus, results in limited water contents and limited drug mobility, resulting in a relatively low drug release rate.

The potential of amorphous solid dispersions to improve the solubility, dissolution rate and bioavailability of poorly water soluble drugs is well known. However, the number of formulations that have made it through to the market is limited because of the unstable nature of the amorphous form, which often results in recrystallization of the drug with the subsequent loss of the solubility and dissolution advantages. Thus, ensuring the stability constitutes a major challenge in the development of amorphous solid dispersions.

Background

The thermodynamic stability of a solid amorphous dispersion can only be ensured by molecularly dispersing (dissolving) the drug in the polymer below its saturation solubility. Therefore, the prediction of drug-polymer solubility at room temperature is of great academic and industrial interest. By assuming that a drug behaves as a solvent for an amorphous polymer it is possible to describe the solubility of a drug in a polymer using the Flory-Huggins model:

where $\Delta H_m$ and $T_m$ are the enthalpy of fusion and melting temperature for the pure drug respectively, $R$ is the gas constant, $\lambda$ is the molar volume ratio of the polymer to the drug, $\chi$ is the Flory-Huggins interaction parameter. $T$ is the temperature at which the measurement is made and $\nu_{\text{drug}}$ is the volume fraction of the drug in the polymer.

However, as the majority of pharmaceutically relevant drugs and polymers are solid, measuring the equilibrium solubility at room temperature is unfeasible. Therefore, several differential scanning calorimetry (DSC) protocols have been proposed based on determination of equilibrium thermodynamics at elevated temperature [1]. In a recently proposed protocol, referred to as the recrystallization method, a supersaturated amorphous solid dispersion is annealed at different temperatures above its glass transition temperature ($T_g$) to recrystallize excess drug and reach equilibrium solubility. The solubility after annealing is then derived from the $T_g$ of the annealed material using the Gordon-Taylor equation and extrapolated using the Flory-Huggins model to predict the solubility at room temperature [2]. Other noteworthy approaches include the melting point depression method [3] and an estimation based on the solubility in a liquid low molecular weight analogue of the polymer [4].

Introducing a confidence assessment

In order to assess the confidence of a prediction it is important to realize which variable is subject to experimental noise. Using the recrystallization method, the temperature ($T$) is the variable under control and can be regarded as free of error whereas the volume fraction of the drug ($\nu_{\text{drug}}$) is subject to error. The optimal estimate for the Flory-Huggins interaction parameter ($\chi$) is thus found by minimizing the sum of squares of the residuals between the observed and predicted $\nu_{\text{drug}}$. Consequently, the confidence of the prediction is expressed as a 95% prediction interval that is dependent on both the inter-replicate variance (reproducibility) and intra-replicate variance (fit to the Flory-Huggins model) [1].

Refining the experimental protocol

The introduction of a formal statistical analysis method enables a comparison of different solubility predictions. In the original method, a milling procedure was used to prepare the supersaturated amorphous solid dispersion [2]. However, as the physical properties and recrystallization behavior of an amorphous material have been reported to be affected by the preparation technique [5], the influence of different preparation techniques (ball milling, spray drying and film casting) on the solubility prediction was investigated [6].

As can be seen in Figure 1, the predicted solubility from the ball milling method is not consistent with those predicted from spray drying and film casting methods, indicating fundamental differences between the three preparation techniques. The most narrow prediction interval was found for spray drying, indicating a combination of a good fit to the Flory-Huggins model and reproducibility of the measurements. The prediction interval for ball milling was wider than that for spray drying, but still relatively narrow. However, as ball milling provided the best reproducibility of the three techniques, the broader prediction interval was a result of a poor fit to the model. In contrast, the broad prediction interval for film casting was a consequence of a poorer reproducibility than for the other two techniques. As previous studies suggest that amorphous mixtures produced by ball milling may still be heterogeneous at the molecular level, the process involved in reaching the equilibrium solubility is most likely driven by dissolution rather than the intentional recrystallization. Therefore, it is recommended that techniques such as spray drying or potentially film casting should be used to prepare the supersaturated amorphous solid dispersions when using this method [6].

Figure 1: Equilibrium solubility of IMC ($\chi_{\text{IMC}}$) in PVP K12 as a function of annealing temperature (Ta). Green diamonds (♦) represent the data from ball milling (a), red circles (●) represents the data from spray drying (b), and blue squares (■) represents the data from film casting (c). The data previously reported by Mahieu et al. (2013) is presented as black crosses (x). The evolution of solubility of the three data sets has been fitted with the Flory-Huggins model (black curves) including the 95% prediction interval (dotted curves). The grey circles (●) represent the experimental relationship between $T_g$ and $\chi_{\text{IMC}}$ and the grey curve is the Gordon-Taylor relationship.

Influence of polymer molecular weight on the prediction

One of the most commonly used carriers for amorphous solid dispersions is polyvinylpyrrolidone (PVP). However, despite the widespread use of PVP, the influence of polymer molecular weight (chain length) on drug-polymer solubility has not been sufficiently elucidated. Only a few studies have addressed this issue and none have supported the theoretical considerations and predictions with relevant experimental data [4]. Therefore, the influence of polymer molecular weight on the predicted solubility using spray drying as preparation technique was investigated [7].

As can be seen from Figure 2, it was found that the predicted solubility was independent of the molecular weight of the polymer. This indicates that the solubility of a given drug-polymer system is determined by the strength of the drug-polymer interactions rather than the molecular weight of the polymer. Therefore, during the initial screenings for drug solubility, only one representative molecular weight per polymer is needed. However, it is important to emphasize that this does not mean that the influence of polymer molecular weight on other important factors such as dissolution rate, physical stability and crystallization inhibition should not be considered in the polymer selection process [7].

Figure 2: Equilibrium solubility of IMC (XIMC) in PVP of different molecular weight as a function of annealing temperature ($T_a$). Red circles (●) represent the data from PVP K12, green squares (■) represent the data from PVP K25, blue diamonds (♦) represent the data from PVP K30, and purple triangles (▲) represent the data for PVP K90. The evolution of solubility of the four data sets has been fitted with the Flory-Huggins model (black curves) including the 95% prediction interval (dotted curves). The grey circles (●) represent the experimental relationship between $T_g$ and $\chi_{\text{IMC}}$ and the grey curve is the Gordon-Taylor relationship.

Conclusions

Knowledge about drug-polymer solubility is an important factor in the development of amorphous solid dispersions as it can ensure the thermodynamic stability of the formulation. Previously, the prediction of drug-polymer solubility was based on a central estimate without an assessment of the confidence of the prediction. By introducing a new dimension to the field in form of formal statistical analysis, we enabled the possibility of comparing different solubility predictions. This can be used advantageously to screen for polymers suitable for amorphous solid dispersions.

Author affiliations

Matthias Manne Knopp and Rene Holm are affiliated with the Department of Pharmaceutical Science and CMC Biologics at H. Lundbeck A/S and Thomas Rades is a Professor in the Department of Pharmacy at the University of Copenhagen. All work has been conducted at H. Lundbeck A/S.

PSSRC Facilities

The research group of Prof. Thomas Rades in Copenhagen focusses on the development of amorphous solid dosage forms including amorphous solid dispersions and co-amorphous formulations. Several methods can be applied to obtain the amorphous form and therefore, the group has extensive knowledge and experience in techniques such as ball milling, spray drying and melt-quenching. In order to assess the stability and physicochemical properties of the formulations, the facilities include XRPD, a range of spectroscopic and microscopic techniques, and state of the art thermal analysis equipment including the DSC, TGA, DMA, and IMC.

For the first time, an appropriate solid dosage form was developed for a co-amorphous drug-amino acid formulation, demonstrating the high physical stability for the particular system during further processing to tablets and during long-term storage thereof.

Background

Co-amorphous drug formulations have been found to be a promising alternative to common solid dispersions. Through this approach, the drug can be stabilized in its amorphous form by interactions with a low molecular weight compound, e.g. another drug or an amino acid [1, 2]. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous drug-amino acid combinations [3]. In the next step, the further processing to a final solid dosage form is of interest.

The aim of this study was to develop an appropriate tablet formulation for spray dried co-amorphous indomethacin-arginine (SD IND-ARG) (see full article). Since compression during tableting poses a crystallization risk, solid-state properties were carefully investigated after tableting with various compaction pressures and after long-term storage. Furthermore, the non-sink dissolution behaviour of tablets with SD IND-ARG (TAB SD IND-ARG) was evaluated in order to assess a possible solubility enhancement. The dissolution profiles were compared to tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND-ARG).

Formulation development

The composition of the tablet formulation for TAB SD IND-ARG and TAB PM IND-ARG is detailed in Table 1. The formulation contained 50 mg IND (according to 74.4 mg SD IND-ARG), mannitol as filler, croscarmellose sodium as superdisintegrant, colloidal silicon dioxide as glidant and magnesium stearate as lubricant. This formulation allowed for the preparation of intact tablets with SD IND-ARG over a broad range of compaction pressures from 42 to 360 MPa. The porosities varied from 29 to 6 %, whereas the tensile strength increased accordingly from 0.8 to 4.5 MPa. All tablets showed an acceptable disintegration time from 4 to 6 min. The requirements of uniformity of dosage units (Ph.Eur. 2.9.40) were also met with a content of 99 ± 2 % and an acceptance value of 5.2.

Physical stability of tablets

The solid-state properties of tablets were investigated by modulated DSC, XRPD and ATR-FT-IR immediately after compaction. Results were compared to those of SD IND-ARG and uncompressed tableting mixtures with SD IND-ARG or PM IND-ARG.

With modulated DSC measurements, a single glass transition temperature was detected between 111 °C and 117 °C for all tablets. This is in agreement with SD IND-ARG powder, which exhibited a glass transition at 114 ± 1 °C [3]. The XRPD pattern (Figure 1A) of the tableting mixtures or tablets, respectively, mainly showed peaks of the filler mannitol. Therefore, characteristic peaks of crystalline IND were selected in order to assess a possible crystallization of amorphous IND from the co-amorphous formulation. Compared to the tableting mixture with PM IND-ARG, there was no evidence of characteristic IND peaks neither in the diffractogram of the tableting mixture with SD IND-ARG nor in diffractograms of the tablets. These results were also obtained after storage for 10 months at 23 °C or 40 °C over silica gel.

Additionally, the specific interactions between drug and amino acid were investigated by ATR-FT-IR (Figure 1B) since they are an essential measure of physical stability. Characteristic for co-amorphous IND-ARG is the formation of ionic interactions, resulting in the disappearance of the peaks at 1690 cm-1 and 1710 cm-1 in the carbonyl stretching region and the appearance of a peak at 1558 cm-1. The latter is related to the stretching vibrations of the COO- group. The spectra of all tablets were comparable to those of SD IND-ARG and the tableting mixture with SD IND-ARG; which indicates that the molecular interactions were not influenced during tableting. Overall, the solid-state characterization of tablets demonstrated the high physical stability of co-amorphous IND-ARG within the tablets and during long-term storage.

Non-sink dissolution behaviour

The dissolution profile of TAB SD IND-ARG is depicted in Figure 2A compared to the profile of SD IND-ARG powder and TAB PM IND-ARG. The results are exemplary shown for tablets pressed with 82 MPa, since the dissolution behaviour was only hardly affected by using different compaction pressures during tablet manufacturing.

The SD IND-ARG powder showed an immediate drug release resulting in a supersaturation by a factor of about 7 (solubility of IND in the dissolution medium: 6.4 mg/L), which was followed by a fast crystallization. In comparison, the drug release from TAB SD IND-ARG was slower due to the reduced surface area of tablets and due to a slow erosion of the tablets. Although the extent of supersaturation was decreased to a factor of about 4, the area under the curve was comparable to SD IND-ARG, because the supersaturation was maintained for a longer period.

Regarding TAB PM IND-ARG, tablets turned yellow directly after contact with the dissolution medium, indicating an in situ amorphization of IND in presence of ARG (Figure 2B). This resulted in a supersaturation, too, whose extent was comparable to TAB SD IND-ARG but which was obtained faster due to the shorter disintegration time of the tablets. A faster crystallization of IND resulted in half the area under the curve.

Interestingly, the plateaus obtained for SD IND-ARG and TAB SD IND-ARG after 24 h dissolution testing were not in accordance with the solubility. This could be explained by the formation of different polymorphic forms of IND.

Polymorph formation during dissolution

To identify the obtained polymorphs, precipitates were investigated by XRPD, DSC and SEM (Figure 3). As expected, diffractograms and thermograms of the precipitates of TAB PM IND-ARG revealed the occurrence of the stable γ-IND. Additionally, SEM images showed the typical prism- and plate-like crystals of the γ-form. This indicates that the in situ amorphization was probably not completely throughout the tablet and, thus, γ nuclei were available resulting in further growth of this polymorph.

Since comparable plateaus were reached during dissolution of SD IND-ARG and TAB SD IND-ARG, the formation of the same modification was expected. The SEM images exhibited needle-shaped crystals for both precipitates, whereas XRPD and DSC indicated the occurrence of different polymorphic forms. SD IND-ARG crystallized in the α-form, which is the most commonly observed metastable modification of IND. The diffractograms and thermograms of the precipitates of TAB SD IND-ARG could not be related to modifications reported in literature. DSC measurements showed that the obtained metastable form melts during simultaneous crystallization to the stable γ-form.

The appearance of different polymorphs obtained from co-amorphous IND-ARG can be explained by varying rates of crystallization, which are influenced by the concentration of dissolved drug. During dissolution of TAB SD IND-ARG, less IND per time was dissolved due to the reduced surface area compared to pure SD IND-ARG powder and due to the slow erosion of the tablet. The resulting lower supersaturation, which was maintained for a longer time, may facilitate the formation of a different polymorphic form.

Conclusion

For the first time, an appropriate solid dosage form was developed for a co-amorphous drug-amino acid formulation, demonstrating the high physical stability for the particular system during further processing to tablets and during long-term storage thereof. The dissolution behaviour of IND was enhanced by the co-amorphization with ARG as well as by formulating the co-amorphous form into tablets. Furthermore, IND was found to crystallize in different polymorphic forms from SD IND-ARG powder or from tablets therewith, which is due to different rates of crystallization.

We have developed a new technique to better understand what happens to the microstructure inside a tablet during rapid disintegration.

Limitations of Disintegration Testing

In traditional disintegration testing it is difficult to establish any detailed insights into the mechanism of tablet disintegration as the test is merely designed to indicate the time it takes for a tablet or capsule to disintegrate completely, and this is defined as the state "in which any residue of the unit [...] is a soft mass having no palpably firm core". Based on the results of the disintegration test it is judged whether or not the dosage form meets the specification required by the respective pharmacopoeia e.g. for immediate release formulations. Apart from establishing the conformity with such official guidelines the disintegration test yields little additional information and is not very useful to guide rational formulation design.

{xtypo_quote_right}New insights for immediate release formulations and new opportunities for PAT measurement techniques{/xtypo_quote_right}

Fast and Non-destructive Imaging of Disintegration

Yassin et al. have introduced an alternative method based on terahertz pulsed imaging (TPI) to advance the understanding of how excipients, the dosage form microstructure and the testing conditions affect the disintegration behaviour in immediate release formulations [1]. The method allows for the first time to quantify the disintegration process on time-scales of seconds by measuring the ingress of the dissolution medium into a tablet with high precision and accuracy. Using this data the authors demonstrate that the disintegration process can be explained using theoretical models much like what is known for controlled release dosage forms. It is possible to investigate in detail how subtle changes in disintegrant concentration or the temperature of the dissolution medium affect the disintegration behaviour.

Figure 1: Disintegration process measured using TPI. The method can resolve both the swelling of the tablet as well as the ingress of the dissolution medium into the tablet.

Subtle Differences in Formulation have Profound Effects

A change in crosscarmellose sodium concentration from 2 to 5 wt% has a dramatic effect on the disintegration kinetics, particularly at a water temperature of 20°C. Here the disintegration time of the tablet is one order of magnitude faster at the higher concentration of superdisintegrant.

The study also highlights the enormous effect of the temperature of the dissolution medium on how rapidly a tablet disintegrates: by changing the temperature from 37°C to 20°C the disintegration time reduced from 25 to 5 seconds in a tablet containing 5% croscarmellose sodium (see Figure 2 below).

Figure 2: Disintegration characteristics of tablets made from MCC and superdisintegrant at different concentrations and water temperature (modified from [1]).

The new method is universally applicable to a wide range of formulations for dosage forms with disintegration times from seconds to hours.

PAT Measurements of Porosity – Non-destructive and Meaningful

In addition the paper highlights that measuring the tablet porosity instead of its hardness is potentially a much better PAT method compared to the time consuming and destructive weight/thickness/hardness testing.

It was previously demonstrated that terahertz spectroscopy is an excellent and very promising tool to non-destructively determine the bulk porosity of a tablet in a simple transmission or reflection experiment [2]. Yassin et al. show that such porosity measurements are very sensitive in resolving the disintegration performance of an actual tablet. Given that the terahertz measurements can be performed on millisecond timescales this technology could be developed into a powerful at-line/on-line or even in-line PAT technique.

Figure 3 (left): THz refractive index can be used as a PAT tool to measure the tablet bulk porosity (modified from [2]).

Background

Terahertz pulsed imaging (TPI) was first introduced in 2007 to non-destructively measure the coating thickness of pharmaceutical tablets. Ever since then, there has been a concerted research effort throughout the PSSRC to further develop and exploit this technique for improving the quality of pharmaceutical coatings and to shed light on the intricacies behind the pharmaceutical tablet coating process.

A notable example of previous work is the use of TPI to monitor the growth of the coating layer during the coating process as an offline technique [1]. The technology was further developed as an inline modality, where unlike the more established techniques such as near-infrared and Raman spectroscopy, TPI could measure coating thickness of individual tablets directly without chemometric models and was able resolve the tablet-to-table thickness distribution inside the coating drum during the coating process [2]. This makes the terahertz technique a unique tool to investigate the microstructure of pharmaceutical tablets as discussed in a previous research highlight.

Validation and Application

In TPI the only material dependent variable that needs to be calibrated in order to measure absolute film thickness is the refractive index of the coating material. The refractive index at terahertz frequencies is different to that at visible frequencies and while it is possible to measure it using terahertz spectroscopy it is important to validate these measurements using an independent technique. In an effort to further demonstrate the applicability of TPI, the method was validated with x-ray microtomography [3] to confirm the assumption that the refractive index is constant, within acceptable error, across the tablet surface for quantifying the absolute coating thickness (Figure 1).

TPI was also demonstrated to quantify active coating processes with active coatings up to 500 µm thick [4]. The applicability of TPI was further shown to work hand in hand with existing techniques, especially as a reference technique in the development of chemometric coating models for in-line Raman spectroscopy of process monitoring and quantification of functional coats [5].

In order to bring users up to speed when using TPI in the context of quantitative pharmaceutical tablet measurement and data analysis, a recent paper [6] presented an extensive discussion on the relevant parameters that need to be controlled so as to not fall into the trap of misinterpreting the TPI measurements. Of a particular mention in this context is the case where active coating is applied to tablets. Interestingly, the refractive index of the active coating was found to change in response to certain process conditions leading to measurement uncertainties when determining the absolute coating thickness. By comparing the content measurements as measured by an HPLC assay and the TPI coating thickness measurements it was possible to establish an excellent correlation between the TPI coating thickness measurement and the drug content in the coating (Figure 2).

Process Understanding

A high level of intra-tablet and inter-tablet coating uniformity are desired attributes in the pharmaceutical film coating process. This is especially the case for tablets receiving functional coats such as sustained release formulations, where a high level of coating variability can potentially undermine the efficacy of the eventual drug product. Even though these attributes are well sought after in the industry, achieving them realistically may prove to be rather difficult.

To date, only a handful of investigations have aimed to identify the process conditions that reliably lead to a reduction in coating thickness variability. TPI, owing to its relatively high spatial resolution, has shown to be a suitable tool for quantifying active coating thickness uniformity of tablets coated under varying process conditions [7, 8]. In particular, using design of experiments (DoE) covering a wide range of realistic coating process conditions for process parameters such as drum load, drum rotation speed, spray rate, spray pressure and coating duration, TPI was used to non-destructively identify and optimise the critical process parameters for an active coating process (Figure 3 and 4). Specifically, it was found that low drum load, high drum rotation speed and long coating durations are factors that could improve intra-tablet and inter-tablet uniformity. Even though a low spray rate was shown to be beneficial for inter-tablet coating uniformity, the same setting would be counter-productive in reducing the level of intra-tablet coating uniformity.

One immediately obvious advantage of the TPI technique for the analysis of active coating processes in this context is the speed and ease of measurement compared to an HPLC content assay: no sample preparation is required, no solvents are used and need to be disposed of and each measurement is completed in well under one hour.

{gallery}tpi_coating{/gallery}

Outlook

In light of recent developments, TPI has further proven to be a robust technology in the field of pharmaceutics with particular advancements made in investigating active coating processes. While the relative immaturity and stability limitations of the technology are barriers for industry-wide adoption, TPI has shown tremendous potential in studying the coating uniformities non-destructively that otherwise would have been difficult to perform, if not impossible, with the existing popular techniques. Future implementations of the TPI as an in-line tool can effectively resolve the inter-tablet inhomogeneities during the coating operation as previously shown [2] and real-time information can be acquired for in-depth process understanding leading to greater control of the process for the production of higher quality dosage forms.

PSSRC Facilities

The group of Dr Axel Zeitler at Cambridge has extensive experience with terahertz technology. The group has a number of custom made THz spectrometers as well as its own commercial TPI coating imaging system (Teraview TPI imaga 2000) and complementing technology to investigate dosage form microstructure, such as a Skyscan X-ray microtomography system.

Professor Peter Kleinebudde’s group in Dusseldorf has a range of film coating equipment and process experience that can be used to simulate realistic process conditions during pharmaceutical film coating. In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Copenhagen, Ghent and Lille.